Amgen Inc.

Tularik Limited

Sharon McKendry

Frank Kayser

Derek Evan Piper

Xian Yun Jiao

Andrew K Shiau

Lawrence R McGee

Jonathan B Houze

Bei Shan

David John Kopecky

Christopher Neil Farthing

John Walter Liebeschuetz

Stephen Clinton Young

Sarah Lively

Stuart Donald Jones

Philippe Bergeron

David Sheppard

Joshua Gergely

Yi Xia

Compounds, compositions and methods are provided that are useful in the treatment or prevention of a condition or disorder mediated by PPAR&#x3b3; or PPAR&#x3b4;. In particular, the compounds of the invention modulate the function of PPAR&#x3b3; or PPAR&#x3b4;. The subject methods are particularly useful in the treatment and/or prevention of diabetes, obesity, hypercholesterolemia, rheumatoid arthritis and atherosclerosis.

Bisaryl-sulfonamides

Bisaryl-sulfonamide compounds having the formula wherein Ar, R, R, L, B, W, X, Y, and Z, compositions and methods are provided that are useful in the treatment or prevention of a condition or disorder mediated by PPAR&#x3b3; or PPAR&#x3b4;. In particular, the compounds of the invention modulate the function of PPAR&#x3b3; or PPAR&#x3b4;. The subject methods are particularly useful in the treatment and/or prevention of diabetes, obesity, hypercholesterolemia, rheumatoid arthritis and atherosclerosis.

The present invention provides compounds, pharmaceutical compositions and methods that are useful in modulating the farnesoid X receptor (FXR). As FXR is involved in negatively controlling the expression level of cholesterol 7&#x3b1;-hydroxylase (cyp7a), the rate-limiting enzyme involved in the oxidative metabolism of cholesterol into bile acids, the compounds described herein find utility in treating diseases associated with abnormally high or low cholesterol levels. In certain aspects, the FXR modulators (e.g., antagonists) described herein block the negative feed-back downregulation of cyp7a expression produced by certain cholic acids, the endogenous ligands for FXR. Moreover, as FXR forms heterodimers with the retinoid X receptor (RXR) in some cell types, modulation of the level of FXR activity in cells has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPAR&#x3b3; and PPAR&#x3b1;. Thus, compounds described herein are useful in treating other biological activities such as obesity, diabetes, lipid associated disorders, cancer, inflammatory disorders, disorders involving a disrupted or dysfunctional epidermal barrier, and various other metabolic disorders.

FXR modulators

Heterocyclic arylsulfonamidobenzylic compounds are provided which are useful in treating lipid disorders, metabolic disorders and cell-proliferative diseases.

Heterocyclic arylsulfonamidobenzylic compounds

Arylsulfonamidobenzyl alcohols, amines and sulfonamides are provided which are useful in treating lipid disorders, metabolic diseases and cell-proliferative diseases.

Arylsulfonamidobenzylic compounds

The present invention provides compounds, pharmaceutical compositions and methods that are useful in modulating the farnesoid X receptor (FXR). As FXR is involved in negatively controlling the expression level of cholesterol 7&agr;-hydroxylase (cyp7a), the rate-limiting enzyme involved in the oxidative metabolism of cholesterol into bile acids, the compounds described herein find utility in treating diseases associated with abnormally high or low cholesterol levels. In certain aspects, the FXR modulators (e.g., antagonists) described herein block the negative feed-back downregulation of cyp7a expression produced by certain cholic acids, the endogenous ligands for FXR. Moreover, as FXR forms heterodimers with the retinoid X receptor (RXR) in some cell types, modulation of the level of FXR activity in cells has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPAR&ggr; and PPAR&agr;. Thus, compounds described herein are useful in treating other biological activities such as obesity, diabetes, lipid associated disorders, cancer, inflammatory disorders, disorders involving a disrupted or dysfunctional epidermal barrier, and various other metabolic disorders.

Growing community of inventors

Redwood Shores, CA, United States of America

Sharon McKendry